A Fly's Perspective on the Human Brain

From high school biology classes to the laboratories of Nobel Prize-winning
geneticists, the halls of science have long valued the Drosophila
melanogaster—the common fruit fly. Despite appearances to the contrary,
this tiny insect is a powerful genetic model for the human system. One reason
for this, explains Nancy
Bonini—Lucille B. Williams Term Professor of Biology and an investigator of the Howard
Hughes Medical Institute—is that Drosophila and Homo sapiens
share a great many of the same genes. And, because fruit flies
have a life cycle of about 10 days, it is possible to study the progression of
genetic diseases and track mutant genes across generations in a highly
compressed time scale.

“These diseases take decades to develop in humans, and take months to years
in mice,” Bonini says. “In flies, we’re talking days—it really puts time on our
side.”

For many years, Bonini’s own lab has been using the fruit fly to address
fundamental mechanisms in long-term maintenance of brain function and
neurodegeneration in humans. When Bonini first joined Penn, the fly had long
been used to study fundamental aspects of human development, but it hadn’t been
used extensively as a model to explore neurodegenerative diseases. Along with
researchers from Penn’s School of
Medicine, she devised an experiment that successfully implanted into
Drosophila the gene that causes SCA3 (spinocerebellar ataxia type 3)
and created transgenic flies that displayed symptoms of the human disease.

SCA3 is a hereditary neurodegenerative disease that typically strikes in
mid-life and causes degeneration in the ability to control muscular movement. It
belongs to a class of progressive, late-onset neurodegenerative diseases,
including Huntington’s, called polyglutamine repeat disorders. In these
disorders, instructions for producing the amino acid glutamine are repeated
excessively in a coding region of the DNA. Normally, the sequence of three
nucleotides that specify glutamine—cytosine, adenine and guanine (CAG)—is
repeated 15 to 20 times. In those suffering from SCA3, the sequence has been
found to repeat as many as four times more than the normal number. The result is
the creation of misfolded proteins that accumulate in the cells of the nervous
system and disrupt cellular operations.

Bonini’s experiments succeeded in producing mutant flies with the same toxic
protein in their brain cells, confirming that the affliction proceeds by similar
mechanisms in the fly as it does in humans. By developing the first model of
human neurodegenerative disease in Drosophila, Bonini set the stage for
a new avenue of research on not only polyglutamine repeat diseases, but other
neurodegenerative diseases like Alzheimer’s and Parkinson’s.

“The idea of using the fly and other simple systems to approach the huge
problem of human neurodegenerative disease has really taken off at Penn and
elsewhere,” Bonini explains.

This year, Bonini published findings that show that faulty RNA containing a
long CAG repeat may contribute to neurodegeneration in polyglutamine repeat
disorders beyond only being the blueprint for misfolded proteins. In performing
a genetic screen for potential contributors to the synthesis of ataxin-3, the
toxic protein associated with the SCA3 disease, Bonini and her team identified a
new gene that dramatically enhanced neurodegeneration. This gene, while not
previously implicated in polyglutamine repeat disorders, was known to contribute
to other classes of diseases that were due to toxic RNA. “This suggested that
what’s coding for the toxic proteins also has a toxicity of its own that causes
problems,” says Bonini.

She and her team then conducted an experiment in which they created the
ataxin-3 protein with RNA that did not use the long CAG repeat sequence. They
found that although the protein produced was identical, the altered gene
resulted in dramatically reduced neurodegeneration, thus implicating the RNA
sequence in the disease progression. Bonini and her team then expressed, in
Drosophila brains cells, RNA with the long CAG repeat sequence that was
unable to code for a protein. They found that neuronal degeneration occurred
even without the presence of the protein.

Bonini says one reason this finding is interesting is because it suggests
commonalities between polyglutamine repeat diseases and other diseases that are
thought to be due to just RNA toxicity.

“If it’s possible to find a therapeutic that works against one of these other
categories of diseases, it may also work for polyglutamine repeat diseases, and
vice versa, because they both have a toxic RNA component,” Bonini explains. “It
also emphasizes the need for therapeutics that could hit both the protein and
RNA, thereby attacking multiple components of the toxicity.”

Bonini’s current research focuses on identifying the mechanisms behind toxic
RNA. “The field of RNA biology has exploded in the past 10 years, and it’s a
whole new world,” she says. “My research is just the tip of the iceberg of our
knowledge about how problems with RNA can cause diseases.”